We report the clinical presentation and genetic screening of a 31-year-old man with dilatation of the aortic root and ascending aorta and a positive family history for aortic dissection and sudden death. A novel heterozygous variant in a splice acceptor site (c.1600-1G>T) of TGFβR2 gene was identified by using a targeted multi-gene panel analysis. Bioinformatics tools predicted that the c.1600-1G>T variant is pathogenic by altering acceptor splice site at − 1 position affecting pre-mRNA splicing. These data confirm that the diverging splicing in the TGF-β pathway genes may be an important process in aneurismal disease and emphasize the utility of genetic sequencing in the identification of high-risk patients for a more patient’s management able to improve outcomes and minimize costs for the care of patients with heritable thoracic aortic aneurysm and dissection.

Keywords:

References

1. Brownstein AJ, Kostiuk V, Ziganshin BA et al. Genes associated with thoracic aortic aneurysm and dissection: 2018 update and clinical implications. Aorta (Stamford) 2018;6:13–20. doi: 10.1055/s-0038-1639612
MedlineGoogle Scholar
2. Isselbacher EM, Preventza O, Black JH III et al. 2022 ACC/AHA guideline for the diagnosis and management of aortic disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2022;80:e223–e393. https://doi.org/10.1161/CIR.0000000000001106
MedlineGoogle Scholar
3. López-Bigas N, Audit B, Ouzounis C, Parra G, Guigó R. Are splicing mutations the most frequent cause of hereditary disease? FEBS Lett. 2005;579:1900–1903. doi: 10.1016/j.febslet.2005.02.047
Medline CASGoogle Scholar
4. Mizuguchi T, Collod-Beroud G, Akiyama T et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat. Genet. 2004;36:855–860. doi: 10.1038/ng1392
Medline CASGoogle Scholar
5. Kurtovic S, Paloschi V, Folkersen L, Gottfries J, Franco-Cereceda A, Eriksson P. Diverging alternative splicing fingerprints in the transforming growth factor-β signaling pathway identified in thoracic aortic aneurysms. Mol. Med. 2011;17:665–675. doi: 10.2119/molmed.2011.00018
Medline CASGoogle Scholar
6. De Cario R, Sticchi E, Lucarini L et al. Role of TGFBR1 and TGFBR2 genetic variants in Marfan syndrome. J. Vasc. Surg. 2018;68:225–233.e5. doi: 10.1016/j.jvs.2017.04.071
MedlineGoogle Scholar
7. Panesi P, Foffa I, Sabina S, Ait Ali L, Andreassi MG. Novel TGFBR2 and known missense SMAD3 mutations: two case reports of thoracic aortic aneurysms. Ann. Thorac. Surg. 2015;99:303–305. doi: 10.1016/j.athoracsur.2014.02.068
MedlineGoogle Scholar
8. Stheneur C, Collod-Béroud G, Faivre L et al. Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys–Dietz syndrome and related disorders. Hum. Mutat. 2008;29:e284–e295. doi: 10.1002/humu.20871
MedlineGoogle Scholar
9. Singh KK, Rommel K, Mishra A et al. TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys–Dietz syndrome. Hum. Mutat. 2006;27:770–777. doi: 10.1002/humu.20354
Medline CASGoogle Scholar
10. Pannu H, Fadulu V, Chang J et al. Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation 2005;112:513–520.
Medline CASGoogle Scholar
11. Tran-Fadulu V, Pannu H, Kim DH et al. Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. J. Med. Genet. 2009;46:607–613. doi: 10.1136/jmg.2008.062844
Medline CASGoogle Scholar
12. Jondeau G, Ropers J, Regalado E et al. International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: results of the MAC (Montalcino Aortic Consortium). Circ. Cardiovasc. Genet. 2016;9:548–558. doi: 10.1161/CIRCGENETICS.116.001485
Medline CASGoogle Scholar
13. Seike Y, Matsuda H, Ishibashi-Ueda H et al. Surgical outcome and histological differences between individuals with TGFBR1 and TGFBR2 mutations in Loeys–Dietz syndrome. Ann. Thorac. Cardiovasc. Surg. 2021;27:56–63. doi: 10.5761/atcs.oa.20-00223
MedlineGoogle Scholar

Ahead of Print

Metrics

Downloaded 5 times

History

Received 21 November 2023

Accepted 26 March 2024

Published online 18 April 2024

Information

Keywords

Author contributions

Material preparation, data collection and analysis were performed by C Vecoli, I Foffa, S Vittorini and N Botto. Clinical and imaging analysis was performed by A Esposito, S Costa, V Piagneri, P Festa and L Ait-Ali. The first draft of the manuscript was written by C Vecoli and I Foffa. All authors commented on previous versions of the manuscript. All authors have read and agreed to the published version of the manuscript.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval and have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish

The authors affirm that human research participants provided informed consent for publication of the images in Figure 3A–C.

PDF download